Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury

Toxicol Appl Pharmacol. 2010 Sep 15;247(3):169-78. doi: 10.1016/j.taap.2010.07.004. Epub 2010 Jul 15.


Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1beta signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1beta formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1beta during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1beta gene transcription but prevented the increase in IL-1beta plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1beta to increase injury, mice were given pharmacological doses of IL-1beta after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1beta formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1beta, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetaminophen / toxicity*
  • Animals
  • CD11b Antigen / biosynthesis
  • Caspase 1 / physiology*
  • Caspase 3 / metabolism
  • Caspase Inhibitors
  • Chemical and Drug Induced Liver Injury / enzymology
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / pathology
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Interleukin-1beta / blood
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology*
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / immunology
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / drug effects
  • Neutrophils / enzymology
  • Neutrophils / immunology
  • Reactive Oxygen Species / metabolism


  • CD11b Antigen
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Interleukin-1beta
  • Reactive Oxygen Species
  • Acetaminophen
  • Caspase 3
  • Caspase 1